Phenyl-alkylamines



United States Patent C PHENYL-ALKYLAMINES Karl Kindler, Hamburg, andHerbert Oelschliiger, Wentorf a.W., Germany, assignors to ChemischeFabrik Promonta G.m.b.H., Hamburg, Germany No Drawing. ApplicationNovember 15, 1955 Serial No. 547,020

Claims priority, application Germany November 15, 1954 7 Claims. (Cl.260247.7)

This invention relates to novel and improved derivatives ofphenyl-alkylamines and it has particular relation to phenyl-alkylamineswhich have a carbon chain of at least two carbon atoms between thephenyl and amine group and are substituted in the benzene radical by analkoxymethyl group, or an aroxymethyl group, or an aralkoxymethyl group.The invention also relates to a process for preparing thephenyl-alkylamines of the beforementioned structure.

The new compounds embodying the present invention are therapeuticallyuseful products and can be used, for example, for local anesthesia.

The compounds of the invention correspond to the following generalformula:

In the above formula R stands for a radical selected from the groupconsisting of alkyl-, aryl-, or aralkyl radicals. X stands for the amineradical and n is an integer which meets the condition n 1. No convenientprocess having good yields, has been hitherto known for the preparationof such amino ethers.

In order to prepare the compounds of the invention, dichlorides of theformula Cl.CH .C H (CH ),,Cl, which can be easily and successfullyprepared by chloromet hylation of phenyl-alkylchlorides of the formulaare first reacted with alkalialeoholates, of alkaliphenolates to formcompounds of the formula and the Cl atom of these compounds is thensubstituted by an amine radical according to conventional methods. Asalcoholates, for example the sodium compounds of primary, secondary ortertiary aliphatic alcohols, aliphatic-aromatic alcohols andalkoxy-alcohols, can be used in this procedure. For example, ethylalcohol, isopropyl alcohol, tertiary butyl alcohol, benzyl alcohol andethoxy ethyl alcohol have been found to satisfactorily react as sodiumalcoholates. Alcohols of high molecular weight, as well as unsaturatedalcohols, such as n-hexyl alcohol, n-octyl alcohol, and allyl alcohol,likewise normally react as sodium alcoholates. From the group of cyclicand heterocyclic alcohols, e.g. cyclohexanol and tetrahydrofurfurylalcohol were used.

From the group of phenolates, the sodium compound of phenol pro-per, aswell as the sodium compounds of its derivatives, which are substitutedeither by electronegative radicals, such as NO -Cl, Br, or byelectroposi- .t ive radicals, e.g. methyl-, isopropylor alkoxy groups,can be used.

In the reactions with members of the phenol series, by way of example,the sodium compounds of the following aromatic hydroxyl-containingcompounds were used: phenol, p-nitrophenol, 2-chlorophenol,4-ch1orophenol, 2,4-diohlorophenol, Z-bromophenol, 4 bromophenol,3-methyl-4-chlorophenol, Z-methyl phenol, 3 methyl Patented Sept. 22,1959 2 phenol, 4-methyl phenol, thymol, 3-methoxy phenol, andfi-naphthol.

The following examples describe some embodiments and best modes ofcarrying out the invention, to which the invention is not limited.

Preparatidn of 4-(chlor0methyl)-B-phenyl-ethyl chloride A mixture of 703parts of B-phenyl ethyl chloride, parts of paraformaldehyde and 75 partsof anhydrous zinc chloride are vigorously stirred for about 45 minutesunder heating to 50 C. in a flask. Subsequently, the reaction mixture iscooled to 30 C. and quickly saturated under strong centrifuging withdried HCl. Care is taken by cooling to prevent the reaction temperaturefrom exceeding 45 C. After saturation, the reaction mixture is allowedto cool under stirring in a weak current of HCl. The contents of theflask is now thoroughly shaken with petroleum ether in a separatingfunnel and the aqueous layer is removed. The layer of petroleum ether iswashed successively with water, NaHCO solution and again with water,dried over calcium chloride, the petroleum ether is distilled off andthe resulting residue is subjected to fractional distillation. In thefirst runnings unchanged ,H-phenyl ethyl chloride is recovered. Inaddition, 326 parts of 4-(chloromethyl)-B-phenyl ethyl chloride having aboiling point =158160 C. are obtained. The yield amounts to 75% of thetheory, calculated on the reacted amount of fi-phenyl ethyl chloride.

Preparation of 4-(chl0romethyl)-'y-phen0l propyl chloride A mixture of773 parts of 'y-phenyl propyl chloride, 75 parts paraformaldehyde and 75parts of anhydrous zinc chloride, is treated by heating to 40 C. understirring, cooling, treatment with dried HCl, subsequent treatment withpetroleum ether in a separating funnel, separation and washing of thelayer of petroleum ether, dis tilling olf the petroleum ether andfractional distillation of the residue, in a manner analogous to thatdescribed in the preceding paragraph in connection with the prep arationof 4-(chloromethyl)-fi-phenyl ethyl chloride. 389 parts of4-(chloromethyl)-'y-phenyl propyl chloride having a boiling point=176178 C. are thus obtained. The yield, calculated on the amount of thereacted 'y-phenyl propyl chloride, amounts to of the theory.

Preparation of 4-(chl0r0methyl)-6-Jphenyl-butyl chloride A mixture of 68parts of fi-p henylbutyl chloride, 6 parts of paraformaldehyde and 4parts of anhydrous zinc chloride is vigorously stirred for 30 minutes,while heated to 50 C. The reaction mixture is then quickly saturatedunder vigorous centrifuging with dry HCl and the reaction temperature isprevented by cooling from exceeding 60 C. After saturation the reactionmixture is allowed to cool under stir-ring in a weak current of HCl.Further processing is carried out in the manner described above inconnection with the preparation of 4-(chloromethyl)-B-phenyl-ethylchloride. The yield of 4-(chloromethyl)-6-phenylbutyl chloride amountsto 79% of the theory, based on the reacted fi-phenylbutyl chloride.Boiling point =169-171 C.

Preparation of N [4- (eth oxymerhyl -'y-ph any l-propyl morpholine 2.3parts of sodium are dissolved in 50 parts of absolute 7 (ethoxymethyD-'-phenyl-propyl' chloride thus 'formed boils at 172-173 C. (20 Torr). Theyield amounts to 93% of the theory.

10 parts of the ether thus obtained are heated with l8 parts ofmorpholine under reflux for 24 hours and occasional stirring to 130 C.and then allowed to cool. After cooling, the reaction mass is mixedwithan excess of hydrochloric acid and shaken once or twice with ether.The acid solution is then rendered alkaline, the amine is extracted andthe extracted amine is subjected to fractional distillation. TheN-[4-(ethoxymethyl)- -phenylpropyll-morpholine boils in the range of162-164 C. (0.4 Torr) and the yield amounts to 79% of the theory.

In an analogous manner, for example the following4-(alkoxymethyl)-phenyl alkamines can be prepared with yields of 80 to90% of the theory.

Preparation of N-[4-(isopr0poxymethyl) w-phenyl-propyll-piperidine 2.3parts of sodium are dissolved under warming in 100 parts of absoluteisopropanol. 24 parts of 4-(chloromethyl)-'y-phenyl-propyl chloride arethen added and the reaction mixture is stirred under reflux at 80 C. for14 hours. Further processing in the manner described above in connectionwith the preparation of N-[4(ethoxymethyl)-' phenyl-propyll-morpholineyields 4-(isopropoxymethyl)-y-phenyl-propy1 chloride in the form of acolourless oil having a boiling point =l72175 C. 11 parts of thiscompound are dissolved in 50 parts of toluene and heated with 17 partsof piperidine to 130 C. under reflux for 24 hours. The piperidinehydrochloride is separated by filtration with suction, and the excesspiperidine and the solvent are removed under moderate vacuum.

The further procedure corresponds to that described above in connectionwith the preparation of N-[4-(ethoxymethyD-y-phenyl-propyllmorpholine.The N-[4-(isopropoxymethyl) 'y phenyl-propyl] -piperidine boils atl62-l64 C. (0.6 Torr).

Preparation of N [4- (tertiary-butoxymethyl -'y-phenyl propyl]-mrph0line 15 parts of tertiary butanol are dissolved in 50 parts oftoluene. 2.3 parts of finely distributed sodium are then introduced andthe liquid is heated to boiling until dissolution is completed. 20 partsof 4-(chlormethyl)- -phenyl-propyl chloride dissolved in 20 parts oftoluene are now dropwise introduced within 60 minutes into said liquidunder stirring at 90 C. and stirring at 90 C. is continued for 48 hours.After cooling, the solvent and the excess of butanol are distilled offunder slight vacuum and the 4-(tertiary-butoxy-methyl)w-phenyl-propylchloride is extracted with ether from the residue. This chloride is ayellowish oil boiling at 226230 C. (13 Torr).

7 parts of this chloride are dissolved in 20 parts of toluene and heatedto 125 C. under reflux with 9 parts of morpholine for 24 hours. Furtherprocessing in the manner described above in connection with thepreparation of N-[4-(isopropoxymethyl) 'y phenyl-propyl]piperidineyields the N-[4-(tertiary butoxymethyD-y-phenyl-propyll-morpholine inthe form of a yellowish oil having a boiling point =198201 C.

Preparation of N-[4-(benzyloxy-methyl)-'y-phenyl-pr0- pyl] -pyrrolidine4.6 parts of sodium are dissolved under Warming in 108 parts of benzylalcohol. Into the resulting liquid 48 parts of 4-(chloro-methyl)w-phenylpropyl chloride are drop-wise added at 75 C. and the reaction mixture isagitated for 6 hours at the same temperature. After cooling the reactionmixture is taken up with ether, the ether layer is washed with water anddried over calcium chloride. The ether is now allowed to evaporate andthe excess of the benzyl alcohol is distilled 0E under water jet vacuum.The residue thus obtained is subjected to pyll-pyrrolidine is subjectedto fractionation.

4 fractionation under 1.5 Torr. The 4-(benzyloxy-methyl)- -phenylpropylchloride distills at 198-200 C.

14 parts of this compound are heated with 14 parts of pyrrolidine in 25parts of toluene to 130 C. for 24 hours. After the reaction iscompleted, toluene and the excess of pyrrolidine are distilled off underslight vacuum. The residue is treated with an excess of 4% hydrochloricacid and the hydrochloric acid solution is washed with ether until itbecomes clear. The amine is precipitated with alkali, taken up withether and the ether layer is dried over potassium carbonate. The otheris then evaporated and the N-[4-(benzyloxymethyl)-q -phenyl-pro- Boilingpoint =l99201 C.

Preparation of N-[4-(ethoxyethyl-oxymethyl)-'y-phenylpropyl] -morpholine 2.3 parts of sodium are dissolved under cooling in 90 parts ofethoxyethyl alcohol. To the resulting liquid 24 parts of4-(chloromethyl)w-phenyl-propyl chloride are added and the reactionmixture is stirred at 80 C. for 8 hours. Further processing in themanner described above in connection with the preparation of N-[4-(ethoxymethyl)-'y-phenylpropyl]-morpholine, yields 4-(ethoxy-ethyloxymethyl)-'y-phenyl-propyl chloride having a boiling point=165l68 C.

13 parts of this chloride are heated with 17 parts of morpholine in 50parts of toluene to 130 C. for 24 hours. Further processing in themanner described above in connection with the preparation ofN-[4-ethoxymethyl) 'y phenyl-propyl]-morpholine yields N-[4(ethoxyethyl-oxymethyl) 'y phenyl-propyl] -morpholine having a boilingpoint =225-226 C.

Preparation of N [4 -(n-hexoxymethyl 'y-phenylpropyl] -m0rph0line 2.3parts of sodium are dissolved by warming in parts of n-hexanol. To thissolution 24 parts of 4- (chloromethyD-y-phenyl-propyl chloride are addedand the reaction mixture is heated under stirring to 70 C. for 6 hours.After cooling, the reaction mixture is diluted with 100 parts of etherand extracted by shaking it several times with water. The solution isdried over sodium sulfate, the other is evaporated and the excess of thehexyl alcohol is distilled oif under water jet vacuum. The residueconsists of 4-(n-l1exoxy-methyl)w-phenyb propyl chloride and boils at203 204 C. (14 Torr).

11 parts of this compound are heated in 25 parts of toluene with 17parts of morpholine under reflux to C. for 24 hours. Further proceedingin the manner described above in connection with the preparation ofN-[4-(isopropoxymethyl) 'y phenyl-propyl] piperidine yieldsN-[4-(n-hexoxymethyl- -phenyl-propyll -morpholine having a boiling pointof 200201 C. (0.6 Torr).

Preparation of N [4-(n-0ct0xymethyl )-'y-phenyl-pr0pyl1- morpholine 33parts of n-octyl alcohol are dissolved in 50 parts of benzene and inthis solution 2.3 parts of sodium are dissolved by warming. Into theresulting solution 24 parts of 4-(chloromethyl)w-phenyl-propyl chlorideare dropwise introduced under vigorous stirring within 30 minutes andstirring is continued with heating to 80 C. for 8 hours. Furtherproceeding in the manner described above in connection with thepreparation of N-[4-(n-hexoxymethyl)-'y-phenyl-propyll-morpholine,yields the 4-(noctoxymethyl) -phenyl-propyl chloride having a boilingpoint=l77-179 C. (0.5 Torr).

15 parts of this compound are heated in 50 parts of xylene with 17 partsof morpholine under reflux to C. for 24 hours. Further proceeding in themanner described above in connection with the preparation of N-[4-Preparation of N [4-( allyloxym ethyl 'y-phenyl-pr0pyl l morpholine 4.6parts of sodium are dissolved under cooling in 116 parts of allylalcohol and to this solution 48 parts of4-(chloromethyl)-'y-phenyl-propyl chloride are dropwise added. Thereaction mixture is then stirred at 80 C. for 7 hours. Furtherproceeding in the manner described above in connection with thepreparation of N-[4-(ethoxymethyl)-'y-phenyl-propy1]morpholine, yields4-(allyloxymethyD -phenyl-propyl chloride having a boiling point =173l75 C.

11 parts of this compound are heated in 50 parts of toluene with 17parts of morpholine under reflux to 130 C. for 24 hours. Furtherproceeding in the manner described above in connection with thepreparation of N- [4-(isopropoxymethyl) 'y phenyl-propyll piperidineyields the N-[4(allyloxymethyl) -phenyI-prQpyIJ-morpholine having aboiling point =191-193 C.

Preparation of N [4 cyclohexoxymethyl -'y-phenyl propyll -m0rpholine 50parts of cyclohexanol are dissolved in 50 parts of benzene and in theresulting solution 2.3 parts of sodium are dissolved by warming. To thissolution 24 parts of 4-(chloromethyl)-' -phenyl-propyl chloride aredropwise added within 30 minutes and the reaction mixture is Preparationof N [4-( tetrahydrofarfuroxymethyl phenyl-propyl] -pyrr0lidine 102parts of tetrahydrofurfuralcohol are mixed with 50 parts of benzene andin the resulting liquid 4.6 parts ofsodium are dissolved. Into thissolution 48 parts of 4-(chloromethyl)-'y-phenyl-propyl chloride aredropwise introduced under stirring and the reaction mixture is stirredat 80 C. for 12. hours. Further proceeding in the manner described abovein connection with the preparation of N-[4-(tertiary butoXymethyD--phenYI- propyll-morpholine, yields after evaporation of the ether thecrude 4-(tetrahydrofurfuroxymethyl)w-phenyl-propyl chloride in the formof an oily residue. 49 parts of this residue are dissolved in 50 partsof toluene and heated With 36 parts of pyrrolidine to 130 C. for 24hours. Further proceeding in the manner described. above in connectionwith the preparation of N-[4-benzyloxymethyl)--phenyl-propyl]-pyrrolidine, yields theN-[4-(tetrahydrofurfuroxymethyl)w-phenyl-propyl]-pyrrolidine having aboiling point =229-23 1 C.

Preparation of N [4- ethoxyethyloxymethyl -;3-pheny lethyl] -m0rph0line213 parts of sodium are dissolved under cooling in 45 parts ofethoxyethyl alcohol. To this solution, which has been heated to 75 C. 23parts of 4-(chloromethyl)-fiphenylethyl chloride ared ropwise addedunder stirring within 60 minutes, and the reaction mixtureis stirred atthe same temperature for 18 hours. Further proceeding in the mannerdescribed above in connection. with the preparation ofN.-[4-(ethoxymethy1) 'y phenyl-propyllmorpholine, yields the 4(ethoxyethyloxymethyl) p phenyl ethyl chloride having a boiling point=1901-' 7 parts of this compound are heated with 17 parts of morpholineunder reflux to. 125 C. for 24 hours. Further proceeding in themannerdescribed above in. connection with the preparation of N-['4-(ethoxymethyD- phenyl-propyl]morpholine, yields theN-[4-ethoxyethyloxymethyl-fl-phenylethyl']-morpholine having a boilingPOinto =221 -2221. C-

Preparation of N- [4-(phenoxymethyl)43-phenylethyl] morpholine 2.3 partsof sodium are dissolved in 50 parts of methanol and to the solution 9.4parts of phenol are added. After addition of thephenol, 23 parts of4-(jchloromethyD-fi-phenylethylchloride are added to the solution, whichis then stirred under reflux at 60 C. for 24 hours. The. methyl alcoholis then distilled off andthe 4-(phenoxymethyl)-B-phenylethyl chloride isextracted from the residue with ether. Thiscompoundhas a boiling pointof 169 l71 C. (0.5 Torr) and forms colorless crystals having a meltingpoint of 4950 C. from petroleum ether. The yield amounts to of thetheory. I

15- parts of this compound are'heated with 43 parts of morpholine underreflux to 125 C. for 24 hours; After this time. the excess morpholine isdistilled off and the amine formed, is purified in conventional mannerover its hydrochloride. The product is obtained from benzene/ petroleumether in the form of colorless crystals having a melting point of 9-1-92C. The yield amounts to about of the theory.

By a similar procedure and in similar yields, other4-(aroxymethyl)-phenyl-alcamines, e-.g. the following compounds areobtained:

Preparation of N-[4-(Z-chlorophenoxymethyl)-B- phenylethyl] -morph0line2.3 parts of sodium are dissolved under cooling in parts of isopropanol.Into this solution 13 parts of o-chlorophenol are introduced and thereaction mixture is heated to 60 C. 23 parts of 4-(chloromethyl) 3-phenylethyl-chlor-ideare now introduced into the solution dropwise understirring Within 30 minutes andthe reaction mixture issti'rreclunderrefiux fora total period of 24 hours. Further proceeding in themanner described above in connection with the preparation ofN-[4-(phenoxymethyl)-B-phenylethyl]-rnorpholine, yields the 4'-(2-chlorophenoxymethyl)-;8-phenylethyl chloride, which has a boiling point=187 -188 C.

18- parts of this compound are heated under reflux with 26 parts ofmorpholine to 125 C. for 24 hours. Further proceeding in the mannerdescribed above in connection with the preparation ofN-[4-(phenoxymethyl) ,B-phenylethyl]-morpholine and purification inconventional manner over its bitartrate, yieldsN-[4-(2-chlorophenoxymethyl)-,8-phenylethyl]-morpholine inthe form ofcolorless crystals from benzene/ petroleum ether. Melting point: 99101C.

Preparation of N-[4-(phenoxymethyl)-'y-phenyl-pr0pyl]'- morpholine64parts of dry sodium phenolate are dissolved in 300 parts ofmethyl-isobutyl-ketone by warming to C. Into this solution 103 parts of4-chloromethyl-y-phenylpropyl chloride are dropwise introduced understirring and stirring is continued at this temperature for a totalperiod of 4 hours. After cooling, the reaction mixture is Washed 2-3times with 100 partsof water and the methylisobutyl ketone is distilledoil under reduced pres.- sure. The residue is taken up in 200 parts ofpetroleum ether and the 4-(phenoxymethyl)' -phenyl-propyl chlo ride iscaused to crystallize by cooling with ice water. The crystals areseparated by filtering with suction and dried at 100 C. undervacuum(:10. Torr) for 1-2 hours,

After-l recrystallization from petroleum ether, the4*(phenoxymethyl)-'y-phenyl-propyl chloride has a melting point of 55 56C.

' 130 parts or this compound are heated under reflux with 130 parts ofmorpholine to 140 C. for 24 hours. Further processing is carried out inthe manner described above in connection with the preparation ofN-[4-(phenoxymethyl) -,B-phenylethyl]-morpholine and yields the N- [4-(phenoxymethyl)-- -phenyl-propyl] morpholine in the form of colorlesscrystals from n-heptane. Melting point: 52-53 C.

Preparation of N-[4-(4-nitro-phenoxymethyl)-'y-phenylpropyll -morpholine4.6 parts of sodium are dissolved under cooling 100 parts of methanol.To the solution 28 parts of 4-nitrophenol are added and subsequently 41parts of 4-(chloromethyD-y-phenyl-propyl chloride are dropwiseintroduced under stirring and heating to 75 C. within 1 hour. Stirringis continued for 48 hours. The methanol is then distilled oil and theresidue is extracted with ether. The ether layer is repeatedly washedwith 4% NaOH solution and subsequently with water and is then dried overcalcium chloride. The ether is now evaporated and the residue subjectedto fractionation. The 4-(4- nitrophenoxymethyl)- -phenyl-propyl chlorideboils at 238-239 C. (0.6 Torr). When obtained from benzene/petroleumether, it has a melting point of 70- 71 C.

31 parts of this compound are dissolved in 50 parts of benzene heated to50 C. and to the solution 17 parts of morpholine in 50 parts of benzeneare dropwise added under stirring. Subsequently, the reaction mixture isheated to 75 C. for 24 hours and then heated to boiling for further 24hours. After cooling the morpholine hydrochloride is filtered off, thereaction mixture washed with water until it is free from morpholine andsubsequently the N-[4-(4-nitro-phenoxymethyl)-v-phenylpropyll-morpholine is extracted with 4% hydrochloric acid. Thehydrochloric acid solution is mixed with ammonia in excess, the amineextracted with ether and the ether layer dried over potassium carbonate.After evaporation of the ether, the desired amine is obtained in theform of colorless crystals. After recrystallization frombenzene/petroleum ether, the crystals have a melting point of 90-91 C.

Preparation of N-[4-(2-chlorophenoxymethyl) -'y-phenylpropyl] -morpholine 4.6 parts of sodium are dissolved under cooling in 100 partsof ethanol. To the solution 26 parts of o-chlorophenol areadded and thereaction mixture heated to 80 C. Into the latter 48 parts of4-(chloromethyl)-'yphenyl-propyl chloride are dropwise introduced understirring and stirring is continued so that the total period of stirringat 80 C. amounts to 8 hours. Further processing is carried out in themanner described above in connection with the preparation ofN-[4-(phenoxymethyD-B-phenylethyl] -morpho1ine. The product thusobtained is the 4-(2-chlorophenoxymethyl)-B-phenylpropyl chloride andhas a boiling point =208 209 C.

15 parts of this compound are heated with 17 parts of morpholine in 25parts of toluene to 140 C. for 24 hours. The morpholine hydrochloride isseparated by filtering with suction, the toluene is distilled off undervacuum and the amine formed is purified in conventional manner over thehydrochloride. The N-[4-(2-chiorophenoxymethyl)---phenyl-propyll-morpholine boils at 229-232 C. (0.6 Torr).

Preparation of N- [4-(4-chlor0-phenoqcymethyl)--, -phenyl- Zpropyll-morphaline Inthe manner described in the preceding example, 2.3

parts of sodium, 13 parts of 4-chlorophenol and 24- parts of4-ehlcromethyl-v-phenyl-propyl chloride are reacted in partsof ethanolto -form'4-(4-chloro-phenoxy methyl)-' -phenyl-propyl chloride. Afterrecrystallization from petroleum ether, this compound melts at 65 C.

7 parts'of this compound are reacted with 17 parts 01. morpholine in 50parts of toluene, in the manner described in't-he preceding example andthereby yield the N [4-(4-chlo-rophenoxymethyl)-'y-phenyl-propyllmorpholine, which can be obtained in the form of colorless crystals fromaqueous methanol, with a melting point of 69-70 C.

Preparation ofN-[4-(2,4-dichl0r0phert0xymethyl)-'yphenyl-propyl]-m0rph0line Thecompound 4-(2,4-dichloro-phenoxymethyl)-'yphenyl-propy-l chloride havinga boiling point =219- 220 C. is prepared by reacting 2.3 parts ofsodium, 16 parts of 2,4-dichlorophenol and 24 parts of 4-(chloromethyl)-' -phenyl-propyl chloride in 100 parts of methanol, in a manneranalogous to that described in the above example relating to thepreparation of N-[4-(2-' chloro-ph enoxymethyl) -phenyl-propyl]-morpholine.

17 parts of the 4-(2,4-dichloro-phenoxymethyl)--,'- phenyl-propylchloride is reacted in 30 parts of toluene with 26 parts of morpholine,this reaction and the subsequent processing being carried out in amanner analogous to that described in the above mentioned example, Theresulting N [4 (2,4 dichloro phenoxymethyl)-'y-phenyl-propyll-morpholine has a boiling point -=28?- 288 C.

Preparation of N [4 (2 bromophenoxymethyl)-'yphenyl-propyl]-m0rpholineThe compound 4-(2-bromo-phenoxymethyl)-- -phenylpropyl chloride having aboiling point =188191 C. is prepared by reacting 2.3 parts of sodium in100 parts of methanol with 17 parts of o-bromo-phenol and 24 parts of4-(chloromethyl)- -pheny1-propyl chloride, in the manner described abovein the example relating to the preparation ofN-[4-(2-chlorophenoxymethyl)-'yphenyl-propyl -morpholine.

21 parts of the 4-(2-bromo-phenoxymethyl)-'yphenylpropyl chloride arereacted in the manner described in said example with 43 parts ofmorpholine in 25 parts of toluene under heating to C. for 24 hours. Theamine formed is purified over the bitartrate. The N-[4- (2 bromophenoxymethyl) 7 phenyl propyllmorpholine boils at 257-262 C. (1 Torr).

Preparation of N [4 (4 bromo phenoxymethyl)-'y-phenyl-propyll-morpholine 2.3 parts of sodium are dissolved in 100parts of ethanol. To the solution 17 parts of p-bromo-p-henol are addedand into the resulting solution, which is heated to 70 C. 24 parts of4-(chloromethyl) y-phenyl-propyl chloride are dropwise introduced within30 minutes under stirring. The reaction time is 3 hours. By furtherproceeding in the manner described in the above example relating to thepreparation of N-[4-(phenoxymethyl 6 phenylethyl] morpholine 4(bromophenoxymethyl)-'yphenyl-propyl chloride is obtained in. the formof colorless crystals from petroleum ether/benzone, with a melting pointof 81 C.

8.5 parts of this compound are heated in 50 parts of toluene with 17parts of morpholine to C. for 23 hours. Further processing takes placesubstantially in the manner described above in the example relating tothe preparation of N-[4-(2-chloro-phenoxymethyl)-phenyl-propyl]-mo1pholine, whereby purification is effected over thebitartrate. TheN-[4-(4-bromo-phenoxymethyl)-'y-phenyl-p-ropyl]-morpholine is obtainedwith a melting point of 77 78 C. from n-heptane in the form of colorlesscrystals.

Preparation ofN-[4-(4-chZero-3-methyl-phen0xymethyl)-'y-phenyl-pr0pyl]-morpholine.

By' reacting 4.6 parts of sodium in 100 parts of methanol with 29 partsof 4-chlor0-m-cresol and 48 parts of 4-(chloro-methyl)-' -phenyl-propylchloride substantially in the manner described in the above examplerelating to preparation of N-[4-(2-chl0ro-phenoxymethyl)-'y-phenylpropyl] -morpholine, as thereaction product 4-(4-chloro- 3.-methyl-p=henoxymethyl)-'y-phenyl-propylchloride is formed. This compound forms colorless crystals frompetroleum ether, having a melting point of 4243 C.

15 parts of this compound are heated in 30 parts of toluene with 17parts of morpholine to 140 C. for 24 hours. Further processing accordingto they above mentioned example yieldsN-[4-(4-chloro-3-methyl-phenoxymethyl) -'yphenyl-propyl]-morpholinehaving a boiling point .=252-253 C.

Preparation of N-E4-(Z-methyl-phenoxymethyl)-y-phenyl-propyll-morpholine 2.3 parts of sodium are dissolved undercooling in 100 parts of methanol. To the solution 13 parts of ocresolare added and into the mixture heated to 75 C., 24 parts of4-(chloromethyl)-' -phenyl-propy1 chlon'de are slowly dropwiseintroduced. The reaction mixture is, stirred for a total period. of 17hours. Further proc-. essing in the manner described in the aboveexample relating to the preparation of N -[4-(phenoxymethyl)-}8-(phenylethyD-morpholine, yields 4-(2-methyl-phenoxymethyD-phenyl-propyl]-chloride having a boiling point 178181 C.

16 parts of this compound are heated with 17 parts of morpholine to 125C. for 24 hours. Further processing according to the above mentionedexample yields N [4 (2 methyl phenoxymet-hyl) 7 phenylpropyll-morpholinehaving a boiling point =220 223 C.

Preparation of N-[4-(S-methyl-phenoocymethyl)-'y-phenylpropyl]-morpholine In a procedure corresponding in every respect to thatdescribed in. the preceding example, m-cresol yields 4- (3-methyl-phenoxymethyl)-' -phenyl-propy1 chloride having a boiling point=l85-l89 C. By reacting this compound with morpholine in the mannerdescribed in the preceding example, N-[4-(3-methyl phenoxymethyl)- 'yphenyl propyl] morpholine having a boiling point =2 28 C. is obtained.

Preparation ofN-[4-(4-methyl-phenovcymethyl)-'y-phenylpropyl]-morpholine Thepreparation of this compound corresponds in every respect to thatdescribed in the above example relating to N-[4-(Z-methyl-phenoxymethyl)-phenyl-propyl] mo-rpholine. In preparing the compound of the present example, first 4 (4-methyl-phenoxymethyl)w-phenyl-propyl chloride having aboiling point =1751-77 C. is formed. The melting point of colorlesscrystals obtained by recrystallization from petroleum ether is 62 C.This compound is reacted with morpholine in the manner described in theabove mentioned previous example, and yields N[4-(4-methyl-phenoxymethyl)-'y-phenylpropyl]-morpholine which formscolorless crystals from petroleum ether, having a melting point of 54 C.

Preparation of N [4 (3 methoxy-phenoxymethyD-yphenyl-pr0pyl]-pyrr0lidine4.6 parts of sodium are dissolved under cooling in 100 parts of ethanol.To this solution first 25 parts of resorcin-monomethyl ether are addedand then 48 parts of 4-(chloromethyl) y-phenyI-propyI chloride are drop-Wise introduced under stirring Within 30 minutes. The reaction mixtureis now slowly heated to 80 C. and kept at this temperature for 8additional hours. After cooling, the sodium chloride is separated byfiltering suction, the ethyl alcohol. is distilled off, the residuetaken up in ether and rendered free fromphenol by washing it with dilute2% sodium hydroxide solution. The ether layer is dried over calciumchloride and then first the solvent and subsequently the byproductconsisting of 4-(ethoxymethyl) y-phenyl-propyl chloride is distilledofli. The residue consists of the crude 4-(3-methoxy-phenoxymethyl)-'y-phenyl-propyl chloride.

48. parts of thiscrude product are dissolved in 50. parts of toluene andheated with 36 parts of pyrrolidine to C. for 24 hours. After cooling,the excess of pyrrolidine and the toluene are distilled ofi under slightvacuum and the residue is purifiedin conventional manner over thehydrochloride. The N-[ 4-(3-methoxy-phenoxymethyl)-'y-phenyl-propyl]-pyrrolidine boils at 232235 C. (0.7 Torr).

Preparation of N [4 4 (6 isopropyl-S-methyl-phenoxymethyl)-'y-phenyl-pr0pyl1-morph0line 2.3 parts of sodium are dissolved in 100.parts of methanol and to this solution 15 parts of thymo-l are addedinto the solution, which. is heated to 75 C., 24,- parts of4-.(chloromethyl) -'y-phenyl-propyl chloride are dropwise introducedunder stirring and. stirring is contiru ed. for 23. additional hours.Further processing carried out in the manner described in the aboveexample relating to the preparation of N-[4-(phenoxymethyl)-[3:phenylethyll-morpholine, yields the4-(6-isopropyl-3jmethyl-phenoxymethyl)- -phenyl-propyl chloride having aboiling point of- 18 6187- C. (0.7 Torr).

16 parts of this compound are heated with. 17.4 parts of morpholine to125 C. for 24. hours. Further processing accordin-gto the abovementioned previous example yields the;N-[4-(6-isopropyl-3-methyl-phen0XY- methyl)-v-phenyl-propyl] morpholinehaving a boiling point =221-223 C.

Preparation of N'-[4-(phenoxymethyl)-'y-phenyl-propyl]- diethylamine 22parts of 4-(phenoxymethyl)-'y-phenyl-propyl chlorideprepared in themanner, described in the above example relating to thev preparation ofN-[4-(phenoxymethyl)-'y-phenyl-propyl]-morpholine are mixed with 37parts of anhydrous dietbylamine and heated to C. in a closed containerfor 24 hours. After cooling the excess of diethylamine is distilled OEand the residue is purified in conventional manner over thehydrochloride. The resulting N-[4-(phenoXymeI-hY-l) -q-phenyl-propyl]-diethylamine boils at 182-1 84 C. (04 Torr).

Preparation 0 N -[4.-(pl.1ea0xymethyl) .-'y-phenylpropyl]methylbatylamine Preparation of N [4-(B-naphthoxymethyl) 'yphenylpropyl] -m0rpholine 2.3 parts of sodium are dissolved in 100 partsof ethanol and to the solution 14 parts of B-naphthol are added. Intothis solution, which is heated to 70 C., 24

parts or 4-(chloromethyl)-' -phenyl-pr0pyl chloride are dropwiseintroduced under stirring Within 30 minutes. Stirring of the reactionmixture is continued for 14 additional hours. By further processing inthe manner described in the above example relating to the preparation ofN-[4 (3 metho xy-phenoxymethyl)y -phenylpropyl] -pyrrolidine, crude 4(,8 naphthoxymethyD-qphenyl-propyl chloride is obtained as a brownishoil.

27 parts of this crude product are dissolved in 50 parts of toluene andheated with 26 parts of morpholine to 140 .C. for 14 hours. Furtherprocessing is carried out in the manner described in the above examplerelating to the preparation ofN-[4-(2-chlorophenoxymethyl)-'y-phenylpropyll-morpholine. The resultingN [4(18-naphthoxymethyl) -'y phenyl propyl] morpholi-ne has a boilingpoint =276279 C.

Preparation of N- [4-(phenoxym'ethyl)-6-phenylbutyl]- morpholine 12parts of sodium phenolate are dissolved in 70 parts of methyl-isobutylketone by heating to 110 C. and into this solution 22 parts ofa-phenylbutyl chloride are dropwise introduced under stirring within 30minutes. The reaction mixture is stirred for 4 additional hours at 110C. and is then allowed to cool. The methyl-isobutyl ketone is distilled01f under reduced pressure and the residue is extracted with ether. Theether layer is washed several times with water and is then dried overcalcium chloride. After evaporation of the other the residue .isdistilled under a pressure of 0.7 Torr, whereby4-(phenoxymethyl)-6-phenylbuty1 chloride distills over at 199203 C.

7 parts of this compound are dissolved in 30 parts of xylene and heatedwith 9 parts of morpholine to boiling under reflux for 24 hours. Afterdistilling oi the excess of morpholine and the xylene, the amine formedis purified in conventional manner over its hydrochloride. The resultingN [4-(phenoxymethyl)-6-pheny1butyl]- morpholine is recrystallized frompetroleum ether and has then a melting point of 49-50 C.

The parts stated above are parts by weight if not otherwise stated. Insome of the above statements of boiling points, the pressure, itdiiierent from one atmosphere, is indicated by a subscript. For exampleB.P. or boiling point means the boiling point at a pres sure of 10 mm.of mercury. The term Torr is a unit of pressure equal to of one normalatmospheric pressure.

It will be understood that the present invention is not limited to thespecific materials, proportions, solvents, conditions and other detailsspecifically described above and can be carried out with variousmodifications. For example, in addition to the amines specificallydescribed other suitable amines and instead of the sodium alcoholatesand phenolates their equivalents, e.g. potassium alcoholates andpotassium phenolates can be used. These and other modifications can bemade without departing from the scope of the invention as defined in theappended claims.

What is claimed is:

1. A new compound corresponding to the general wherein R stands for aradical selected from the group. consisting of ethyl, isopropyl,t-butyl, allyl, cthoxyethyl, benzyl, phenyl, oresyl radicals andradicals of hexanol, octylalcohol, cyclohexanol, tetrahydrofurfurylalcohol, monochlorophenol, monobromophenol, dichlorophenol,mononitrophenol, monochloro-cresol, beta-naphthol, resorcinmonomethylether and 3-"hydroxy-4-isopropyl'tolu ene; n is an integer in the rangeof 2-4 and -NX is an amino radical selected firom the group consistingof mor-' pholine, piperidine, pyrrolidine, diethylamine, and methylbutylamine radicals.

2. As a new compound, N- [4-(ethoxymethyl)-'y-phenylpropyl] -morpholine.

3. As a new compound, N-[41isopropyloxymethy1)-7-phenylpropyll-piperidine.

4. Asa new compound, N-[4-(ethoxyethyloxymethyl)-fi-phenylpropyl]-morpholine.

5. As a new compound, N- [-4-(phenoxymethyD-yphenylpropyll-morpholine.

6. As a new compound, N-[4-(phenoxymethyl) -6-phenylbutyll-morpholine.

7. A process for preparing a compound corresponding to the generalformula ownQ-(omnm wherein n has the meaning defined above, with asubstance selected from the group consisting of alkali alcoholates andalkali phenolates, in order to react it with the Cl atom of thechloromethyl group and heating the resulting product with an amine inorder to replace the second Cl atom by the amine radical.

References Cited in the file of this patent UNITED STATES PATENTS1,793,176 Klarer Feb. 17, 1931 OTHER REFERENCES Kindler et -al.: Archivder Pharmazie und Berichte der deutschen pharmazertischen Gesellschaft,vol. 283, pp. 184-1190 (1950), abstracted in Chemical Abstracts, vol.45, cols. 19704971 (1951).

1. A NEW COMPOUND CORRESPONDING TO THE GENERAL FORMULA
 2. AS A NEWCOMPOUND, N-(4-ETHOXYMETHYL)Y-PHENYLPROPYL)-MORPHOLINE.